3-acylamino-4-carboalkoxy-2-omega-ralkylthiophenes



Patented Apr. 4, 1950 UNITE j STATES PATENT OFFICEs-ecizimvnuo-4-oARBoALKoxY-2-w-n- ALKYLTHIOPHENES Lee C. Cheney, Syracus7 Pienin-g, Detroit, Mich,

e, N. Y., and John Robert assignors to Parke,

Davis & Company; Detroit; Mich, a. corpora.

tion "of. Michigan I I fNofDrawinaQ dri'gi'nal application Decemben 213,

1944', Serial-No. plieation April 8,

R in these formulas represents a radical of the class --COOH, -COOM,alkoxy, aralkoxy and aryloxy, where M is a salt-forming basic groupor'metal, such. as-sodium or. other alkali metal, alkaline earth metal,magnesium, ammonium and substituted ammonium, such as monoalkylammoniumand dialkyIam-monium. R is lower alkyl; R"CO- is an organic; carboxylicacid acyl radical. I

The starting materials for this invention, namely the3-amino-4-carboalkoXy-2 o-substitutedalkyl) thiophenes-may be preparedby methods disclosed in ou'rcopending application, Serial No. 569,639,filed December 23, .1944; now Ratent No. 2,443,598 issued June 22,1948.

The following examples illustrate the invention. Example 1 red with"dilutexhydmchloric acic1,,.and extracted removal of solvent by steamdistil1a.

569,640. Divided and this am 1946, Serial No. 660,402

5 Claims. (01. zed-329) twice with ether. Combined ether extracts. aredried with anhydrous sodium sulfate, the ether is evaporated and theresidue, is shaken with 200 ml. of petroleum etl ier (B. 1?. 35-60 C.)for the removal of benzoic acid. The resulting light tan solid isfiltered. Recrystallizatiorrfrom dilute alcohol yields 2.77 g. (81%) ofcream-colored needles. M. P. 12.6.5-1275" C. having the iorrnulacioooira I .("';--!NHC 0.00m HI) c rorenc'oonf Ami-cared. forC19H21O5NS2- c, 60.77 1-1.5..63;

' Found". C, 60.70; H, 5.53.

Example 2 I Ethyl 3 benzoylamino-zhitenorypmpylflthiophene-cdrboasylateH-To a warm solution of 14.1 g.(6.046 mole) of 3-amino-4-carbethoxy- 2 -pheno-xypropyl-thiophene, M. P.56-57 C. 100. ml. of-glacial acetic acid is added 100; ml. of. a.saturated solution of sodium acetate. The WQHQ: stirred. suspension iscooled in an ice bath; and. 11ml. (9.7; g.) (0.069'rnole) of benzoylchloride.- is added dropwise. Lumps of solid soon separate. Afterstirring; for so min tes the suspension is. filtered and. washed withice water. The granular. product is dissolved "in 180 ml. of hot glacialacetic acid, treated with 70 ml. of a saturated solution of sodiumacetate, cooled in ice and again treated with 8 ml. of benzoyl chloride.As soon as the suspension solidifies'the ice bath is removed, 50 ml..of. Wateris. added andthe mixture 1 is stirred at room temperature for3.5,hours'. Then 100 ml. of Water is added and the suspension is cooled.filtered, washed with cold water-and desiccated in vacuum over P205.Crystallization. from alcohol'following Dal-co treatment produces 15.7g; (83%. yield) offine ivory crystals. M. P.1- 9798' 'C. A sample. ofthe compound is. re crystallized from alcohol (Darco) as colorlessneedles, M. P. 98-99 C. Anal.-Calcd. for C23H23O4NS2 C, 67.5.; 11.5.66;Found: C. 67.38; H.591. Its. formula is.

tliiophene carboxylateswi mixture of. 2.79 g,-

after filtering from Darco and is treated with hot water until a faintturbidity remains. When cool, an oil separates out. Addition of a largevolume of water precipitates more oil. After scratching and cooling forseveral hours "the product begins to crystallize, yielding a tanmaterial which is collected, dried and Weighed. The weight of crudematerial is' 3.4 g., yield 92%, M. P. 60 C. A sample is recrystallizedthree times from 80% ethanol to a melting point of 6566 C.

Anal. Calcd. for C24H25O4NS: N, 3.31%. Found: N, 3.44%.

Its formula is,

The 3-amino-4-carbethoxy-2-thiophenevaleric acid used in Example 1 as astarting material can be made from ethyl 3-amino-4-carbethoxy-2-thiophenevalerate of M. P. 43-44 C. as described in copendingapplication of Lee C. Cheney and John Robert Piening, Serial No.569,639, filed December 23, 1944. This 44 C. melting compound isprepared from the oxime of ethyl 4- carbethoxy 3 keto 2tetrahydrothiophene valerate by treatment of a dry ether solution ofthelatter with dry hydrogen chloride gas, converting the aminehydrochloride to the amine with alkali bicarbonate, and finallypartially hydrolyzing the amine to the mono-ester. The oxime mentionedis made from ethyl 4-carbethoxy 3 keto 2 tetrahydrothiophenevalerate andhydroxylamine hydrochloride by the known procedure for producing oximesfrom their corresponding ketones. The 3-keto compound is, in its turn,made from the action of dry sodium ethylate in dry-benzene onp-carbethoxyethyla,w-dicarbethoxyamyl sulfide of formula,

The cyclic 3-keto compound can be purified by way of its copper chelatesalt.

The above mentioned sulfide is obtainable by reacting an alkalinesolution of ,B-mercaptopro- All of the above reactions for making theintermediate of Example 1 and also-analogous inter: mediates for theother examples are described in United States applications of Lee C.Cheney and John Robert Piening, Serial No. 550,483" and Serial No.550,484, filed August 21, 1944, both now abandoned, and Serial No.551,619, filed August 28, 1944. I l n Numerous variations from the aboveexamples, which are nevertheless within the scope of the:

invention, will occur to those skilled in the art- For example, in' thefirst step wherein the 3- amino group is converted to an amide group,any

suitable organic carboxylic acid acylating agent may be used, such asacetyl chloride, acetic anhydride, phenyl acetyl chloride, naphthoylchloride aswell as benzoyl chloride.

What we claim as our invention is: 1. A compound of the formula,

where the alkyl chain, OnH2n, consists 'of from 1 to 8 carbon atoms, andR is a radical of the class consisting of COOH, COOM, alkoxy; aralkoxyand aryloxy, M being a salt-forming group.

3. A compound of the formula,

NH-COOeHn no dcHm-oooH s 4. A compound of the formula,

NHC 00am 5. A compound of the formula, C O 0 C3115 I Nn cooim LEE C.CHENEY.

' JOHN ROBERT PIENING.

REFERENCES CITED The following references are of record in the file ofthis patent:

Karrer: Helv. Chim. Acta, vol. 27, pages '133 and 134, Feb. 1, 1944.

Shriner and Fuson, Identification of Organic:

76 Compoundspage 117, Wiley, N. Y., 1935. I

1. A COMPOUND OF THE FORMULA,